In this application we propose to develop microRNA and ultraconserved non coding RNA (UCR) biomarkers for the assessment of cancer risk and for the early detection of five different epithelial cancers, including the four most common malignant tumors (lung, breast, prostate, and colorectal cancer). A major reason, if not the major reason, of why these common epithelial tumors cause so much death and fail to respond to treatment is that by the time they are detected and diagnosed, the malignant cells have accumulated a large number of genetic and epigenetic alterations and have often acquired a "mutator" phenotype. During the past five years, we have established the microRNA expression profiles and, in some cases the UCR expression profiles, of the major human epithelial malignancies. On the basis of this extensive experience, now we intend to assess whether microRNA and UCR dysregulation can be detected in the serum of individuals at risk of developing cancer and at risk of cancer progression in order to develop non invasive biomarkers of cancer risk and for early detection. Such biomarkers could then be also exploited to follow the success of therapy.